PD is a progressive neurodegenerative disorder of unknown etiology that results in the loss of dopamine neurons projecting from substantia nigra to striatum. My colleagues and I have shown that if a cast is placed on the ipsilateral limb during the first 7 days prior to or following unilateral 6-OHDA infusion, forcing reliance on the impaired contralateral limb, both the behavioral and neurochemical deficits are reduced (Tillerson et al, 2001; 2002; Cohen et al, 2003). The mechanism underlying the protective effect of forced limb use is unknown. However I have shown that GDNF, a potent dopaminotrophic factor that protects against 6-OHDA toxicity (e.g., Kearns and Gash, 1995; Choi-Lundberg et al, 1998), is increased with forced limb use, indicating that it may be involved in the protective effects of forced limb use against 6-OHDA (Cohen et al, 2003). Although the mechanism by which GDNF might exert its protective effects is also unknown, evidence suggests that GDNF acts in part through the Ras/ERK signaling cascade (eg: Soler et al., 1999). The specific aims for this project are: Aim 1: Determine the impact of prior forced limb use on the anatomical state of DA neurons after 6-OHDA. Aim 2: Determine if the ERK signaling cascade is involved in forced-limb use-induced increases in GDNF and resulting neuroprotection. Aim 3: Determine the relationship between increases in GDNF in the striatum and the neuroprotective effects of forced limb use.